Breast Cancer : Targets and Therapy最新文献

Objective: The standard treatment for locally advanced breast cancer (LABC) is neoadjuvant therapy combined with surgery with chemotherapy as the main means. Elderly female patients often lose treatment opportunities due to the cardiotoxicity and other intolerable adverse reactions of chemotherapy drugs and their inoperability. Most breast cancers originate from the epithelial cells lining the ducts of the breast. We proposed that for the treatment of LABC, intraductal infusion of chemotherapeutic drugs could lead to high local exposure of the drug to the mammary ducts and avoid systemic toxicity. In order to verify its safety, we conducted a series of studies.

Methods: We perfused two different chemotherapeutic drugs into the mammary ducts of pigs or dogs, observed their skin toxicity and measured the drug distribution and concentration in tissues and blood. Strictly select clinical cases, perform intraductal chemotherapy, and observe their skin toxicity and systemic toxicity. In addition, drug transport pathways in the breast of Beagle dogs were clarified by combining contrast-enhanced magnetic resonance imaging (MRI) with gadolinium dimeglumine injection with advanced image processing techniques and computational fluid dynamics (CFD) simulations.

Results: In animal experiments, no grade II ~ IV skin toxicity related to perfusion drugs was observed. Strictly screened clinical cases significantly reduced tumor lesions by intraductal chemotherapy, and no significant cutaneous or systemic toxicity was observed. Validated models showed that the transport of contrast agent within the breast ducts mainly relies on convection and diffusion mechanisms, and convection shows a significantly higher transport efficiency than diffusion.

Conclusion: This study demonstrates the safety and feasibility of intraductal chemotherapy, provides preliminary data supporting the further investigation of intraductal chemotherapy as a potential local treatment strategy for LABC patients who cannot tolerate intravenous chemotherapy and cannot be operated on, and provides a valuable theoretical and computational basis for the selection of delivery routes and pharmacokinetic analysis of anticancer drugs.

Registration details: This trial was approved by the Ethics Committee of Pudong Hospital Affiliated to Fudan University [Clinical Trial Number: (2021) Ethics Approval No. (QWJWZY-01)].

Purpose: This study aimed to evaluate the real-world outcomes and treatment patterns of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine therapy (ET) for hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC), as well as the use and effectiveness of later-line therapies, in a single tertiary center in Poland.

Patients and methods: This retrospective, single-center study included 661 patients who initiated CDK4/6 inhibitor-based therapy between September 2019 and December 2023. Data were extracted from medical records to assess progression-free survival (PFS), chemotherapy-free survival, and treatment trajectories. Statistical analyses included Kaplan-Meier estimates and Log rank tests for survival outcomes.

Results: The majority of patients (80%) received CDK4/6 inhibitors as first-line therapy, predominantly combined with aromatase inhibitors. Median PFS was 25.8 months overall, with superior outcomes observed in the first-line setting (29.0 months vs 13.8 months in second-line; p < 0.0001). AI-based combinations outperformed fulvestrant in the first line (38.9 vs 16.8 months; p < 0.0001). Chemotherapy-free survival of patients treated in the first line with CDK4/6 inhibitors reached 39.1 months. After progression on first-line CDK4/6 inhibitors, 71% received second-line treatment (49% chemotherapy, 35% ET); median PFS was 4.2 vs 5.3 months, respectively. Only 31% received third-line treatment (median PFS: 3.1 vs 2.6 months).

Conclusion: CDK4/6 inhibitors continue to provide substantial clinical benefit in routine practice, with evolving treatment strategies reflecting growing emphasis on individualized, less toxic approaches. A notable shift from chemotherapy towards targeted and endocrine therapies in later lines underscores the changing landscape of ABC management. However, the outcomes in the later lines of therapy are still unsatisfactory. Enhancing biomarker testing is critical for advancing precision oncology in this setting.

Objective: To investigate the relationship between the C-reactive protein-albumin-lymphocyte index (CALLY) and clinicopathological characteristics, as well as its prognostic value in stage III breast cancer patients.

Methods: A retrospective analysis was conducted on the clinicopathological data of 187 stage III breast cancer patients who were treated in our hospital from 2010 to 2015. The optimal cut-off value for CALLY index was determined by ROC curve. Chi-square tests and Fisher's exact tests were used for intergroup analysis. Survival curves were plotted using Kaplan-Meier method, and comparisons between groups were made using Log Rank test. Univariate and multivariate analyses were performed using the COX regression model. A nomogram prediction model was constructed based on the results of multivariate analysis and validated using the concordance index (C-index), calibration curves, and decision curve analysis (DCA).

Results: According to ROC curve, the optimal cut-off value for CALLY was determined to be 0.10, dividing the patients into a low CALLY group (54 patients) and a high CALLY group (133 patients). CALLY was identified as a potential independent prognostic factor for stage III breast cancer patients. Patients with high CALLY values had longer survival time than those with low CALLY values (DFS: χ² = 9.109, P = 0.0025; OS: χ² = 5.637, P = 0.0176). The C-indices for the nomograms predicting DFS and OS were 0.692 (95% CI: 0.541-0.811) and 0.730 (95% CI: 0.586-0.838), respectively. The calibration curves showed excellent calibration performance for predicting 1-year and 3-year DFS and OS. Decision curve analysis revealed that the nomogram model had better clinical performance than the CALLY model in predicting 3-year, 5-year, and 10-year DFS and OS.

Conclusion: CALLY index is a potential independent prognostic factor for stage III breast cancer patients. It provides new insights and methods for clinical diagnosis and treatment of breast cancer.

Purpose: Increasing evidence supports the critical role of immune cell infiltration in breast cancer progression. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming during polarization, which is vital for immune responses. Here, we screened for genes associated with TAMs infiltration and involved in tumor metabolism, and investigated their expression and effects in breast cancer.

Patients and methods: Bioinformatics analysis was used to screen genes related to immune cell infiltration and involved in tumor metabolism. Immunohistochemistry (IHC) was performed to validate the expression of selected target genes. Multiplex immunohistochemistry (mIHC) was applied to investigate the localization and expression relationship between target genes and TAMs. Real-time quantitative PCR (qRT-PCR) was used to detect the expression of target genes in TAMs. The Human Protein Atlas was utilized for single-cell clustering analysis of breast cancer to assess the expression patterns of target genes, while also evaluating the correlation between target genes and immune checkpoint expression.

Results: Database analysis revealed that Indoleamine2,3-Dioxygenase1 (IDO1) and Interleukin 4 Induced 1 (IL4I1) are highly expressed in breast cancer, with their expression closely associated with immune cell infiltration, particularly macrophage infiltration, which exhibited the highest infiltration rate. IHC analysis revealed that both IDO1 and IL4I1 were expressed in breast cancer, which were mostly located in TAMs. mIHC co-localization demonstrated that IDO1 and IL4I1 were both expressed in TAMs, and qRT-PCR results confirmed increased expression of IDO1 and IL4I1 in TAMs. Single-cell analysis of breast cancer revealed that IDO1 and IL4I1 were most highly expressed in c-19 macrophages, and their expression was positively correlated with most immune checkpoints.

Conclusion: This study suggests that IDO1 and IL4I1, which are involved in tumor metabolism, may play an important role in regulating TAMs immune infiltration in breast cancer. Therefore, IDO1 and IL4I1 are potential therapeutic targets for breast cancer.

Research purpose: To investigate how dexmedetomidine (DEX) controls the proliferation and death of breast cancer cells.

Methods: Human breast cancer cells were cultured in vitro with DEX at different concentrations (25, 50, 100 ng/mL) or 30 μM LY294002. Cancer cell viability, proliferation, apoptosis and the expression of Microtubule-associated protein light chain 3 (LC3)-II/LC3-I protein were separately analyzed using cell counting kit 8 (CCK-8), colony formation, flow cytometry and Western blot assays after DEX treatment. The effect of DEX on mitochondrial membrane potential (MMP) level in cancer cells was determined using immunofluorescence. The expressions of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K, protein kinase B (AKT) and p-AKT in DEX-treated cancer cells were measured by Western blot.

Results: DEX promoted cell growth activity and proliferation, inhibited cell autophagy and apoptosis and down-regulated the ratio of LC3-II/LC3-I to reverse the effect of LY294002 on breast cancer cells. DEX also abrogated LY294002-induced down-regulation of MMP, p-PI3K/PI3K, p-AKT/AKT and Bcl-2 and up-regulation of Bax in breast cancer cells.

Conclusion: DEX may promote the development of breast cancer cells while preventing cancer cell autophagy and apoptosis in vitro via PI3K/AKT signaling.

Background: The immune response plays a critical role in determining the prognosis of breast cancer (BC) patients. However, the underlying molecular mechanisms linking immune regulation to BC progression remain uncleared. This study aims to identify and functionally validate key immune-related genes that mechanistically impact on BC prognosis.

Methods: We used the Mendelian randomization (MR) integrating genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data to prioritize candidate genes with a potential causal role in BC-related immune traits. This study was designed to establish a robust genetic rationale for candidate selection, minimizing false positives. Subsequent analyses focused on DAAM1, genes highlighted by the MR analysis, to explore their clinical relevance and biological functions. We validated their expression and association with immune infiltration levels using LASSO regression and patient tissue samples. Functional roles of DAAM1 were further investigated through in vitro assays based on cell proliferation, adhesion, invasion, and migration. The underlying mechanism was illustrated via Western blotting.

Results: Our integrated MR analysis identified DAAM1 as a top candidate with a genetically supported link to BC immune traits. DAAM1 expression was significantly elevated in BC tissues and inversely correlated with immune infiltration levels, suggesting a role in modulating the tumor immune microenvironment. Functional experiments demonstrated that DAAM1 knockdown effectively suppressed BC cell proliferation, adhesion, invasion, and migration. Mechanistically, Western blot analysis revealed that DAAM1 promotes these malignant phenotypes potentially through activating the epithelial-mesenchymal transition (EMT) pathway.

Conclusion: This study identified DAAM1 as a key immune-related prognostic biomarker in breast cancer, whose upregulation contributes to tumor progression and metastasis via EMT pathway. Our findings, elaborated in a causal inference framework, provide a mechanistic basis for DAAM1's role in BC and underscore its potential as a therapeutic target.

Purpose: This study aimed to evaluate differences in tumor characteristics, molecular subtypes, and surgical approaches between elderly (≥70 years) and younger (<70 years) breast cancer patients.

Patients and methods: This retrospective, single-center study analyzed 120 breast cancer patients (99 younger, 21 elderly) treated surgically between 2020 and 2025 at Istanbul Aydın University, Turkey. Tumor characteristics and surgical management related data were analyzed to compare two age groups. Statistical analyses included t-tests, chi-square tests, and Fisher's exact tests.

Results: Elderly patients presented with significantly larger tumors (3.91±0.56 vs 2.81±0.35 cm, p<0.05), higher T4 disease prevalence (19.05% vs 3.37%, p<0.05), and greater metastatic burden (7.90±6.06 vs 3.54±4.49 metastases, p<0.05). SLNB was performed significantly more frequently in younger patients (90.9%) compared to elderly patients (71.4%, p < 0.05). Elderly patients underwent axillary dissection in 57.1% of cases compared to 33.3% in younger patients. Advanced tumors (T3+T4) were more prevalent in elderly patients with Luminal B HER2-positive (33.3% vs 0%, p<0.0001) and Luminal B HER2-negative (37.5% vs 8.3%, p<0.05) subtypes. Surgical management differed significantly between groups: mastectomy was performed more frequently in elderly patients (57.14% vs 31.31%, p<0.05), whereas breast-conserving surgery was less common (42.9% vs 67.7%, p<0.05).

Conclusion: These findings demonstrate important differences in disease presentation and surgical management between age groups in Turkey, where breast cancer screening ends at age 69. The absence of screening detection in elderly patients, combined with their advanced disease presentation, highlights the need for further investigation with larger, multicenter cohorts to evaluate optimal screening strategies for women beyond age 69.

Purpose: To investigate the effect of modified Shuyu pill on the timing of TNBC metastasis, MDSCs recruitment in tumor tissues and distant target organs, and the impact on the JAK2/STAT3 signaling pathway.

Methods: The fingerprint profile of the modified Shuyu pill was obtained using UPLC-Q-Exactive HRMS technology. A TNBC-bearing mouse model was established, and the mice were treated with modified Shuyu pill granules (low, medium, and high doses), paclitaxel (PTX), or saline for 25 days. Tumor growth was monitored during treatment, and small animal in vivo imaging was performed on days 1, 7, 14, 21, and 25. On day 21 of treatment, flow cytometry was used to assess the proportion of G-MDSCs and M-MDSCs in peripheral blood, spleen, lungs, and tumor tissues. Immunofluorescence was used to detect the number and distribution of MDSCs in the lungs and liver. Western blotting and RT-qPCR were used to detect the expression of proteins and genes related to the JAK2/STAT3 signaling pathway in tumor tissues.

Results: The modified Shuyu pill inhibited tumor growth and distant metastasis in 4T1 tumor-bearing mice, and its anti-tumor effect was enhanced when combined with paclitaxel. More importantly, modified Shuyu pill suppressed the recruitment of MDSCs in the peripheral blood, spleen, lungs, liver, and tumors of tumor-bearing mice, thereby inhibiting the formation of the pre-metastatic niche. Mechanistically, modified Shuyu pill inhibited the expression of proteins in the JAK2/STAT3 signaling pathway, including IL-6, JAK2, p-JAK2, STAT3, p-STAT3 (Tyr705), p-STAT3 (Ser727), S100A8, S100A9, NF-κB, MMP2, and MMP9, and this effect was more pronounced when combined with paclitaxel.

Conclusion: The modified Shuyu Pill can downregulate the JAK2/STAT3 signaling pathway, reduce the number of MDSCs in the tumor microenvironment and distant lung tissues of tumor-bearing mice, inhibit the formation of pre-metastatic niches, and ultimately suppress tumor growth and metastasis.

Background and purpose: Breast cancer presents a substantial clinical challenge because of its complex aetiology and diverse phenotypic presentations. ST6Gal1 expression and epithelial-to-mesenchymal transition (EMT) frequently lead to metastasis, drug resistance and poor prognosis in many cancers. Nevertheless, the molecular details surrounding ST6GAL1 in the carcinogenesis of breast cancer, especially in the EMT of breast cancer, remain unclear. The objective of this study was to clarify the possible role and mechanism of ST6GAL1 in breast cancer.

Methods: PCR, WB, and IHC were employed to analyze the expression of ST6GAL1, epithelial-mesenchymal transition (EMT) markers, and components of the HIF-HK2 signaling pathway in MCF-10A, MDA-MB-231, and MCF-7 cells. Wound-healing, cell adhesion, drug resistance and extracellular matrix invasion assays were used to analyse the effects of ST6GAL1 on the biological process of breast cancer cells. The HIF-HK2 signalling pathway was also analysed.

Results: ST6GAL1 expression is increased in breast cancer. Altered expression of ST6GAL1 affects the biological function of breast cancer cells both in vitro and in vivo. ST6GAL1 knockdown inhibited EMT in breast cancer cells. ST6GAL1 Mediates the Activity of the HIF-HK2 Signalling Pathway in Breast Carcinoma Cells.

Conclusion: In our study, in vitro and in vivo models revealed that ST6GAL1 promotes malignant phenotypes in breast cancer cells and regulates the EMT process through activation of the HIF-HK2 signalling pathway.

Background: Inflammatory bowel disease (IBD) and breast cancer represent significant global health burdens. Although epidemiological studies have suggested a potential link between them, the causal relationship and underlying molecular mechanisms remain unclear. This study employed Mendelian randomization (MR) and multi-omics approaches to investigate the causal association between IBD and breast cancer and to explore shared genetic biomarkers and pathological pathways.

Methods: A two-sample MR analysis was performed using genome-wide association study (GWAS) data. Shared genes were identified and validated using the GEO and TCGA databases. THBS3 expression was further verified in human breast cancer tissues via immunohistochemistry and RT-PCR. Immune infiltration analysis, drug sensitivity assessment, molecular docking, ceRNA network construction, and pathway enrichment analyses (GSEA and GSVA) were conducted to explore the functional role of THBS3.

Results: MR analysis indicated that IBD significantly increases the risk of breast cancer. THBS3 was identified as a commonly overexpressed gene in both diseases and was associated with poor prognosis. THBS3-high breast cancer patients exhibited resistance to Dinaciclib, Daporinad, and Rapamycin. Molecular docking and dynamics simulations confirmed a strong binding affinity between THBS3 and Rapamycin. A ceRNA network linked THBS3 to miR-423-5p and chemotherapy resistance-related lncRNAs. Pathway analyses revealed THBS3 involvement in extracellular matrix receptor interaction and proteasome pathways.

Conclusion: This study provides genetic evidence supporting IBD as a risk factor for breast cancer and highlights THBS3 as a key shared biomarker. THBS3 may promote breast cancer progression through immune regulation, ECM remodeling, and drug resistance mechanisms, suggesting its potential as a therapeutic target. These findings support enhanced breast cancer screening in IBD patients.